Although great advances have been made in the methods used for treating cancer patients, significant problems remain. In general, cancer is treated using surgery, chemotherapy, radiation therapy, or a combination of these methods. Surgical methods, however, can be curative only when the cancer detected early and has not metastasized. Similarly, radiotherapy, when used, generally only is effective when a tumor is localized. In many cases, however, a cancer has metastasized by the time it has been diagnosed and, therefore, chemotherapy, which provides a systemic treatment, is indicated, sometimes in combination with surgery or radiotherapy. In most cases, chemotherapy suffers from the disadvantage that it generally is not specific for the cancer cells, but also kills rapidly dividing normal cells. In fact, toxicity to normal cells generally limits the dose of chemotherapy that a patient can tolerate. In other cases, a hormonal therapy can provide a more specific treatment, for example, for treating breast cancer where the breast cancer cells express an estrogen receptor. However, cancer cells often become resistant to a chemotherapeutic, including hormonal, agent and, therefore, become refractory to the treatment.
Immunotherapy holds great promise for treating cancer because it can be effective against disseminated disease and because, in theory, it can directed only against the cancer cells. Immunotherapy can be active or passive. For active immunotherapy, a tumor antigen is administered to a patient, resulting in the generation of an immune response against the antigen and against cancer cells expressing the antigen. For passive immunotherapy, an antibody against a tumor antigen, for example, is raised separate from the patient, and is administered to a patient having a cancer that expresses the antigen used to raise the antibody.
Efforts at active immunotherapy of melanoma, for example, have been attempted using crude vaccines composed of “killed” melanoma cells isolated either from the patient to be treated or from another patient, or of lysates or extracts of such cells. However, the use of crude vaccines for immunotherapy is problematic, in part, because the precise antigenic composition of such vaccines is largely undefined. It is generally believed that more effective immunotherapy requires the identification and isolation of proteins that are expressed relatively specifically by cancer cells, preferably on their surface, but are not expressed on normal cells. However, such cancer cell specific antigens are rare and have been difficult to identify.
Many cancers are characterized, in part, by an overexpression of an otherwise normal protein, and efforts to target these overexpressed proteins using immunotherapeutic methods have been attempted. For example, the Her2/neu protein can be overexpressed in breast cancer cells, and passive immunotherapy using a monoclonal anti-Her2/neu antibody, Herceptin® antibody, has shown a clinical benefit. However, the use of Herceptin® antibody can result in the development of ventricular dysfunction and congestive heart failure and, therefore, requires careful monitoring of a treated patient. Such methods of passive immunotherapy also have inherent problems. For example, administration of an antibody as a passive immunotherapy procedure can result in an immune response generated by the patient against the administered antibody and can result in an anaphylactic reaction. Also, an administered antibody has a finite lifetime in a patient and, therefore, must be administered several times over a course of treatment. As such, active immunotherapy against a protein expressed by a cancer cell would be a preferred method of cancer treatment. Unfortunately, as discussed above, few cancer specific proteins have been described. Thus, a need exists to identify tumor antigens that can be used to stimulate an active immune response by a patient against the cancer, without producing undesirable toxicity to normal cells in the patient. The present invention satisfies this need and provides additional advantages.